Transcription factors mediate long-range enhancer-promoter interactions
Transcription factors mediate long-range enhancer-promoter interactions
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DOI：
10.1073/pnas.0902454106
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发表时间：
2009-12-01
影响因子：
11.1
通讯作者：
Thanos, Dimitris
中科院分区：
文献类型：
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作者：
Nolis, Ilias K.;McKay, Daniel J.;Thanos, Dimitris
我们研究了远程增强子如何与靶启动子建立物理通信以激活基因转录以响应环境信号。尽管天然的IFN-β增强子紧邻核心启动子的上游，但它也可以作为经典的增强子元件，赋予异源启动子的病毒感染依赖性激活，即使它位于距离这些启动子几千个碱基的地方。我们证明了远程IFN-β增强子“环出”插入DNA以到达靶启动子。这些染色质环依赖于与增强子和启动子结合的序列特异性转录因子，因此可以解释在增强子-启动子相互作用中观察到的特异性，特别是在复杂的遗传基因座中。分散在增强子和启动子之间的转录因子结合位点可以作为诱饵，将增强子捕获在非生产性环中，因此类似于绝缘子元件。最后，将参与DNA成环的转录因子结合位点替换为能够形成环的异源原核蛋白（λ阻遏物）的结合位点，通过重新建立增强子-启动子环的形成从远处拯救增强子功能。
We examined how remote enhancers establish physical communication with target promoters to activate gene transcription in response to environmental signals. Although the natural IFN-beta enhancer is located immediately upstream of the core promoter, it also can function as a classical enhancer element conferring virus infection-dependent activation of heterologous promoters, even when it is placed several kilobases away from these promoters. We demonstrated that the remote IFN-beta enhancer "loops out" the intervening DNA to reach the target promoter. These chromatin loops depend on sequence-specific transcription factors bound to the enhancer and the promoter and thus can explain the specificity observed in enhancer-promoter interactions, especially in complex genetic loci. Transcription factor binding sites scattered between an enhancer and a promoter can work as decoys trapping the enhancer in nonproductive loops, thus resembling insulator elements. Finally, replacement of the transcription factor binding sites involved in DNA looping with those of a heterologous prokaryotic protein, the lambda repressor, which is capable of loop formation, rescues enhancer function from a distance by re-establishing enhancer-promoter loop formation.